Although spontaneous immune responses against tumor-associated antigens (TAAs) (Hrouda et al. (1999) Semin. Oncol. 26: 455-471) can be detected (Disis et al. (1997) J. Clin. Oncol. 15: 3363-3367), malignant cells causing disease fail to elicit an immune response that leads to rejection. Many studies have demonstrated that it is possible to enhance the immunogenicity of tumor cells by introducing immunostimulatory molecules such as cytokines and costimulatory molecules into them (Dranoff and Mulligan (1995) Adv. Immunol. 58: 417-454; Hrouda et al. (1999) Semin. Oncol. 26: 455-471; Hurford et al. (1995) Nat. Genet. 10: 430-435); however, effective gene transfer still remains a challenge. In addition, eradication of residual cancer cells may require the targeting of widely scattered micrometastatic tumor deposits that are not accessible to direct gene transfer.
Both the innate and the adaptive immune responses are essential for providing protection against infectious pathogens and tumors. The cross-talk between innate and adaptive immunity is regulated by interactions between cells and cytokines. Cytokines produced by cells of the innate immune system can, directly or indirectly, activate the cells of the adaptive immune response and can play an important role in eliciting protective antitumor immunity (Belardelli and Ferrantini (2002) Trends Immunol. 23: 201-208). Central to the activation of the innate immune system is the detection of bacterial products or “danger” signals that lead to the release of proinflammatory cytokines, such as IFN-α, TNF-α, and IL-1.
IFN-α is a proinflammatory cytokine with potent antiviral and immunomodulatory activities and is a stimulator of differentiation and activity of dendritic cells (DCs) (Santini et al. (2000) J. Exp. Med. 191: 1777-1788). Type I IFNs (IFN-α and IFN-β) have multiple effects on the immune response (Theofilopoulos et al. (2005) Annu. Rev. Immunol. 23: 307-336). IFN-α plays a role in the differentiation of Th1 cells (Finkelman et al. (1991) J. Exp. Med. 174: 1179-1188) and the long-term survival of CD8+ T cells in response to specific antigens (Tough et al. (1996) Science 272: 1947-1950).
Multiple studies have shown that IFNs are also capable of exerting antitumor effects in both animal models (Ferrantini et al. (1994) J. Immunol. 153: 4604-4615) and cancer patients (14. Gutterman et al. (1980) Ann. Intern. Med. 93: 399-406). In addition to enhancing the adaptive antitumor immune response, IFN-α can increase expression of the tumor suppressor gene P53 (Takaoka et al. (2003) Nature 424: 516-523), inhibit angiogenesis (Sidky and Borden (1987) Cancer Res. 47: 5155-5161), and prime apoptosis (Rodriguez-Villanueva and McDonnell (1995) Int. J. Cancer 61: 110-11417) in tumor cells. Although these properties suggest that IFN-α should be an effective therapeutic for the treatment of cancer, its short half-life and systemic toxicity have limited its usage.